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The references to be discussed throughout this document are set forth merely for the information described therein prior to the filing dates of this document, and nothing herein is to be construed as an admission, either express or implied, that the references are xe2x80x9cprior artxe2x80x9d or that the inventors are not entitled to antedate such descriptions by virtue of prior inventions or priority based on earlier filed applications.
The present invention is directed to the treatment of B cell lymphoma using chimeric and radiolabeled antibodies to the B cell surface antigen Bp35 (xe2x80x9cCD20xe2x80x9d).
The immune system of vertebrates (for example, primates, which include humans, apes, monkeys, etc.) consists of a number of organs and cell types which have evolved to: accurately and specifically recognize foreign microorganisms (xe2x80x9cantigenxe2x80x9d) which invade the vertebrate-host; specifically bind to such foreign microorganisms; and, eliminate/destroy such foreign microorganisms. Lymphocytes, amongst others, are critical to the immune system. Lymphocytes are produced in the thymus, spleen and bone marrow (adult) and represent about 30% of the total white blood cells present in the circulatory system of humans (adult). There are two major sub-populations of lymphocytes: T cells and B cells. T cells are responsible for cell mediated immunity, while B cells are responsible for antibody production (humoral immunity). However, T cells and B cells can be considered as interdependentxe2x80x94in a typical immune response, T cells are activated when the T cell receptor binds to fragments of an antigen that are bound to major histocompatability complex (xe2x80x9cMHCxe2x80x9d) glycoproteins on the surface of an antigen presenting cell; such activation causes release of biological mediators (xe2x80x9cinterleukinsxe2x80x9d) which, in essence, stimulate B cells to differentiate and produce antibody (xe2x80x9cimmunoglobulinsxe2x80x9d) against the antigen.
Each B call within the host expresses a different antibody on its surfacexe2x80x94thus, one B cell will express antibody specific for one antigen, while another B cell will express antibody specific for a different antigen. Accordingly, B cells are quite diverse, and this diversity is critical to the immune system. In humans, each B cell can produce an enormous number of antibody molecules (ie, about 107 to 108). Such antibody production most typically ceases (or substantially decreases) when the foreign antigen has been neutralized. Occasionally, however, proliferation of a particular B cell will continue unabated; such proliferation can result in a cancer referred to as xe2x80x9cB cell lymphoma.xe2x80x9d
T cells and B cells both comprise cell surface proteins which can be utilized as xe2x80x9cmarkersxe2x80x9d for differentiation and identification. One such human B cell marker is the human B lymphocyte-restricted differentiation antigen Bp35, referred to as xe2x80x9cCD20. xe2x80x9d CD20 is expressed during early pre-B cell development and remains until plasma cell differentiation. Specifically, the CD20 molecule may regulate a step in the activation process which is required for cell cycle initiation and differentiation and is usually expressed at very high levels on neoplastic (xe2x80x9ctumorxe2x80x9d) B cells. CD20, by definition, is present on both xe2x80x9cnormalxe2x80x9d B cells as well as xe2x80x9cmalignantxe2x80x9d B cells, ie, those B cells whose unabated proliferation can lead to B cell lymphoma. Thus, the CD20 surface antigen has the potential of serving as a candidate for xe2x80x9ctargetingxe2x80x9d of B cell lymphomas.
In essence, such targeting can be generalized as follows: antibodies specific to the CD20 surface antigen of B cells are, eg, injected into a patient. These anti-CD20 antibodies specifically bind to the CD20 cell surface antigen of (ostensibly) both normal and malignant B cells; the anti-CD20 antibody bound to the CD20 surface antigen may lead to the destruction and depletion of neoplastic B cells. Additionally, chemical agents or radioactive labels having the potential to destroy the tumor can be conjugated to the anti-CD20 antibody such that the agent is specifically xe2x80x9cdeliveredxe2x80x9d to, eg, the neoplastic B cells. Irrespective of the approach, a primary goal is to destroy the tumor: the specific approach can be determined by the particular anti-CD20 antibody which is utilized and, thus, the available approaches to targeting the CD20 antigen can vary considerably.
For example, attempts at such targeting of CD20 surface antigen have been reported. Murine (mouse) monoclonal antibody 1F5 (an anti-CD20 antibody) was reportedly administered by continuous intravenous infusion to B cell lymphoma patients. Extremely high levels ( greater than 2 grams) of 1F5 were reportedly required to deplete circulating tumor cells, and the results were described as being xe2x80x9ctransient.xe2x80x9d Press et al., xe2x80x9cMonoclonal Antibody 1F5 (Anti-CD20) Serotherapy of Human B-Cell Lymphomas.xe2x80x9d Blood 69/2:584-591 (1987). A potential problem with this approach is that non-human monoclonal antibodies (eg, murine monoclonal antibodies) typically lack human effector functionality, ie, they are unable to, inter alia, mediate complement dependent lysis or lyse human target cells through antibody dependent cellular toxicity or Fc-receptor mediated phagocytosis. Furthermore, non-human monoclonal antibodies can be recognized by the human host as a foreign protein; therefore, repeated injections of such foreign antibodies can lead to the induction of immune responses leading to harmful hypersensitivity reactions. For murine-based monoclonal antibodies, this is often referred to as a Human Anti-Mouse Antibody response, or xe2x80x9cHAMAxe2x80x9d response. Additionally, these xe2x80x9cforeignxe2x80x9d antibodies can be attacked by the immune system of the host such that they are, in effect, neutralized before they reach their target site.
Lymphocytes and lymphoma cells are inherently sensitive to radiotherapy for several reasons: the local emission of ionizing radiation of radiolabeled antibodies may kill cells with or without the target antigen (eg, CD20) in close proximity to antibody bound to the antigen; penetrating radiation may obviate the problem of limited access to the antibody in bulky or poorly vascularized tumors; and, the total amount of antibody required may be reduced. The radionuclide emits radioactive particles which can damage cellular DNA to the point where the cellular repair mechanisms are unable to allow the cell to continue living; therefore, if the target cells are tumors, the radioactive label beneficially kills the tumor cells. Radiolabeled antibodies, by definition, include the use of a radioactive substance which may require the need for precautions for both the patient (ie, possible bone marrow transplantation) as well as the health care provider (ie, the need to exercise a high degree of caution when working with the radioactivity).
Therefore, an approach at improving the ability of murine monoclonal antibodies to be effective in the treatment of B-cell disorders has been to conjugate a radioactive label or toxin to the antibody such that the label or toxin is localized at the tumor site. For example, the above-referenced IF5 antibody has been xe2x80x9clabeledxe2x80x9d with iodine-131 (xe2x80x9c131Ixe2x80x9d) and was reportedly evaluated for biodistribution in two patients. See Eary, J. F. et al., xe2x80x9cImaging and Treatment of B-Cell Lymphomaxe2x80x9d J. Nuc. Med. 31/8:1257-1268 (1990); see also, Press, O. W. et al., xe2x80x9cTreatment of Refractory Non-Hodgkin""s Lymphoma with Radiolabeled MB-1 (Anti-CD37) Antibodyxe2x80x9d J. Clin. Onc. 7/8:1027-1038 (1989) (indication that one patient treated with 131I-labeled IF-5 achieved a xe2x80x9cpartial responsexe2x80x9d); Goldenberg, D. M. et al., xe2x80x9cTargeting, Dosimetry and Radioimmunotherapy of B-Cell Lymphomas with Iodine-131-Labeled LL2 Monoclonal Antibodyxe2x80x9d J. Clin. Onc. 9/4:548-564 (1991) (three of eight patients receiving multiple injections reported to have developed a HAMA response); Appelbaum, F. R. xe2x80x9cRadiolabeled Monoclonal Antibodies in the Treatment of Non-Hodgkin""s Lymphomaxe2x80x9d Hem./Onc. Clinics of N.A. 5/5:1013-1025 (1991) (review article); Press, O. W. et al xe2x80x9cRadiolabeled-Antibody Therapy of B-Cell Lymphoma with Autologous Bone Marrow Support.xe2x80x9d New England Journal of Medicine 329/17: 1219-12223 (1993) (iodine-131 labeled anti-CD20 antibody IF5 and B1); and Kaminski, M. G. et al xe2x80x9cRadioimmunotherapy of B-Cell Lymphoma with [131I] Anti-B1 (Anti-CD20) Antibodyxe2x80x9d. NEJM 329/7 (1993) (iodine-131 labeled anti-CD20 antibody B1; hereinafter xe2x80x9cKaminskixe2x80x9d).
Toxins (ie, chemotherapeutic agents such as doxorubicin or mitomycin C) have also been conjugated to antibodies. See, for example, PCT published application WO 92/07466 (published May 14, 1992).
xe2x80x9cChimericxe2x80x9d antibodies, ie, antibodies which comprise portions from two or more different species (eg, mouse and human) have been developed as an alternative to xe2x80x9cconjugatedxe2x80x9d antibodies. For example, Liu, A. Y. et al., xe2x80x9cProduction of a Mouse-Human Chimeric Monoclonal Antibody to CD20 with Potent Fc-Dependent Biologic Activityxe2x80x9d J. Immun. 139/10:3521-3526 (1987), describes a mouse/human chimeric antibody directed against the CD20 antigen. See also, PCT Publication No. WO 88/04936. However, no information is provided as to the ability, efficacy or practicality of using such chimeric antibodies for the treatment of B cell disorders in the reference. It is noted that in vitro functional assays (eg, complement dependent lysis (xe2x80x9cCDCxe2x80x9d); antibody dependent cellular cytotoxicity (xe2x80x9cADCCxe2x80x9d), etc.) cannot inherently predict the in vivo capability of a chimeric antibody to destroy or deplete target cells expressing the specific antigen. See, for example, Robinson, R. D. et al., xe2x80x9cChimeric mouse-human anti-carcinoma antibodies that mediate different anti-tumor cell biological activities,xe2x80x9d Hum. Antibod. Hybridomas 2:84-93 (1991) (chimeric mouse-human antibody having undetectable ADCC activity). Therefore, the potential therapeutic efficacy of chimeric antibody can only truly be assessed by in vivo experimentation.
What is needed, and what would be a great advance in the art, are therapeutic approaches targeting the CD20 antigen for the treatment of B cell lymphomas in primates, including, but not limited to, humans.
Disclosed herein are therapeutic methods designed for the treatment of B cell disorders, and in particular, B cell lymphomas. These protocols are based upon the administration of immunologically active chimeric anti-CD20 antibodies for the depletion of peripheral blood B cells, including B cells associated with lymphoma; administration of radiolabeled anti-CD20 antibodies for targeting localized and peripheral B cell associated tumors; and administration of chimeric anti-CD20 antibodies and radiolabeled anti-CD20 antibodies in a cooperative therapeutic strategy.